Effectiveness and safety of high-dose cyclophosphamide as salvage therapy for high-risk multiple myeloma and plasma cell leukemia refractory to new biological agents.

Multiple Myeloma (MM) patients refractory to bortezomib and one or more immunomodulatory drugs have a poor clinical outcome. Alkylating agents are often avoided in the initial management of MM in part due to concerns for impairment of HSC mobilization. High doses of cyclophosphamide (HiCy) administered without HSC support may be an effective treatment to rescue MM patients refractory to novel biological agents. We performed a retrospective single institution analysis of 17 consecutive MM patients receiving high dose cyclophosphamide (HiCy, 3000 mg/m2) after failure of bortezomib and, in most cases, at least one immunomodulatory agent (IMiD). Despite the prevalence of high-risk features in this cohort we found HiCy to be an effective salvage therapy for high-risk MM patients refractory to new biological agents. Multiple Myeloma (MM) is a malignant plasma cell disorder with no standard curative therapy [1] affecting 4.3 per 100,000 individuals yearly in the united states, accounting for about 1% of all cancers and 10% of all hematological malignancies [2]. Patients who receive conventional chemotherapy or autologous stem cell transplantation have a mean overall survival of 3.7 years [1], although survival is likely increasing with the assimilation of new biological agents into the management of MM [3-7]. For decades, melphalan and prednisone were the cornerstones of MM management. Complete responses under this regimen are rare, and the median time for progression is not higher than 15 months [5, 8]. The immunomodulatory (IMiD) drugs thalidomide and lenalidomide [6, 7] along with the first proteasome inhibitor bortezomib have shown efficacy in managing relapsed and refractory MM [4, 9, 10]. These biological agents have been quickly incorporated in the upfront management of MM so that regimens containing one or more biological agents have produced the highest response rates ever reported for previously untreated MM patients [3, 11-19]. Despite these advances, patients refractory to, or progressing after, treatment with one or more biological agents have a very poor prognosis and no satisfactory therapeutic option [12, 20]. A recent study from the International Myeloma Working Group reported the outcomes of 270 patients relapsing on or refractory to bortezomib and one IMiD. Only 30% of the patients had an objective response to the next line of therapy. The median overall survival and event free survival time were dismal eight months and five month, respectively [12]. With the enthusiasm generated by autologous hematopoietic stem cell transplantation (HSCT) and the new biological agents, alkylating agents are often excluded from the initial therapy of MM and patients failing new biological agents are often alkylating-naïve. High-dose, single agent cyclophosphamide can be an attractive alternative in this setting since it does not require stem cell support and is compatible with poor renal function. In this report we present a retrospective analysis of consecutive patients with bortezomib-refractory (and most IMiD-refractory) MM treated with high-dose cyclophosphamide and growth factor support at our institution. A total of 17 patients treated between March 2009 and January 2011 were included in the analysis. Characteristics of the patients are displayed in Table I. The median age of patients was 53 years (range, 26–73) and the median time from initial diagnosis until cyclophosphamide treatment was 17.3 months (range, 1.6–106.4). Patients were heavily pretreated with the median number of prior treatments being 3 (range, 1–6). All patients were refractory to the last therapeutic regimen and had failed to respond or were refractory to a regimen containing bortezomib. Twelve patients (70.6%) had previously received at least one IMiD and three patients (17.6%) had previously received autologous HSC transplantation. Six patients (35.3%) met criteria for plasma cell leukemia at the time of cyclophosphamide treatment and eight (47.1%) had renal dysfunction at the time of treatment including two patients on chronic hemodialysis. The patients included in the series were not eligible for any trials available at the institution or in the area due to one or more of the following reasons: advanced renal dysfunction (n = 8), plasma cell leukemia (n = 6), ECOG performance status >2 (n = 5) or bortezomib refractoriness (n = 17). Median follow up was 4.2 months (range, 1.7–21.4) from cyclophosphamide administration. Response was assessed four to six weeks after administration of cyclophosphamide. Overall, nine patients had a partial response or better (52.9%, 95%C.I. 29.2–76.7%), including 4 patients with a very good partial response (23.5%, 95%C.I. 3.4–43.7%). All the remaining patients had stable disease. Five of the 12 patients previously treated with at least one IMiD obtained a response (41.6%) along with 4/7 patients previously treated with an alkylating agent (57.1%). Median overall survival was 14.1 (±7.1) months (see Fig. 1). Interestingly, all six patients with plasma cell leukemia had complete clearance of plasma cells from the peripheral blood. Among the 12 patients with intent to proceed with HSCT (cyclophosphamide used as “bridge” therapy), eight patients underwent either autologous (n = 7) or allogeneic (n = 1) transplantation. The median survival for these patients is estimated at 21 months. The remaining four patients did not receive HSCT because of refusal (n = 1), fast disease progression (n = 2), or worsening performance status and comorbidities (n = 1). Overall, eight patients have died, one due to toxicity of treatment and seven from disease progression. Proportion of refractory multiple myeloma patients surviving after treatment with high-dose cyclophosphamide over time (months). Median overall survival was 14.1 months (±7.1). Alkylating agents are an important component of both conventional and high-dose chemotherapy-based treatment of MM. In recent years, due to the enthusiasm about new biological agents and the concerns regarding impairment of future HSC mobilization, alkylating agents have often been avoided in the initial management of MM. We believe that many of the patients becoming refractory to proteasome inhibitors and IMiDs were still sensitive to alkylating agents and could be rescued with high-dose cyclophosphamide without HSC support. There are few series on the management of MM refractory to proteasome inhibitors and IMiD [21]. These patients should be urged to participate in clinical trials with new drugs, including new proteasome inhibitors, histone deacetylase inhibitors, anti-CS1 antibodies and third generation IMiDs. A recent report including 270 “double refractory” patients from the Multicenter International Myeloma Working Group indicates a median survival of eight months from the time the patients failed last therapy. Remarkably, only 30% of patients had an objective response to the subsequent line of therapy [12]. Even though the present series include higher proportions of patients with Stage 3 disease at the diagnosis, unfavorable chromosomal abnormalities, and 3 or more prior lines of therapy, objective response (partial response or better) was documented in 52.9% of the patients. Another interesting observation is that all six patients with plasma cell leukemia had clearance of circulating plasma cells within four weeks of administration of cyclophosphamide. Comparisons between our series and the much larger series by Kumar et al. [12] requires caution due to the small sample size, lower proportion of patients refractory to an IMiD (70.6 vs. 100%) and lower proportion of patients with prior autologous hematopietic stem cell transplantation (17.6 vs. 74%). There are significant limitations of this therapy that need to be emphasized. Despite antibiotic prophylaxis and growth factor support, the majority of patients developed fever and neutropenia requiring hospitalization, and one patient died from complications of sepsis. This is therefore a toxic regimen requiring careful patient selection. The most important limitation however is the short duration of the responses obtained. In fact, all responding patients either died as consequence of disease progression or required subsequent therapy within three months of receiving cyclophosphamide. This aspect is responsible, at least in part, for the short median overall survival despite the considerable rate of objective responses. We suggest therefore that cyclophosphamide can be used as a “bridge” strategy for more definitive therapy, particularly in patients needing immediate disease control. The most important point of the current report is that in the era of biological agents and deferred use of alkylating agents, many patients who become “double refractory” are still sensitive to alkylating agents. Although high doses of cyclophosphamide is one valid option to explore such sensitivity, combination of cyclophosphamide and biological agents may be a safer and equally successful approach [19, 22]. In fact, there is justifiable enthusiasm for the potential of bortezomib to inhibit NF-κB mediated activation of the Fanconi/BRCA pathway and enhance DNA damage induced by alkylating agents [23]. In summary, high doses of cyclophosphamide can transiently control high-risk MM refractory to novel biological agents. Clinical trials are necessary to redefine the best use of alkylating agents in MM in a therapeutic landscape dominated by safe and highly active biological agents. This is a retrospective single institution review of all consecutive patients with bortezomib-refractory MM treated with high-dose cyclophosphamide at the Medical University of South Carolina. Inclusion criteria were firm diagnosis of symptomatic MM, prior disease progression while receiving therapy or within 60 days of completing therapy with a bortezomib containing regimen, and intent to treat with high doses of cyclophosphamide without hematopoietic stem cell (HSC) support. Treatment consisted of cyclophosphamide 3,000 mg/m2 administered over 1 hr. The dose of cyclophosphamide was fractioned in two days (1,500 mg/m2/day) for patients receiving outpatient therapy. All patients, with the exception of two anuric patients in chronic dialysis, received mesna for prophylaxis of hemorrhagic cystitis (20% of the cyclophosphamide dose at 0, 4, and 8 hr of cyclophosphamide infusion). All patients received antibiotic prophylaxis with ciprofloxacin, acyclovir, and fluconazole and growth factor support with peg-filgrastim. We obtained Institutional Review Board approval to perform this analysis. Data extracted included de-identified patient demographics, disease characteristics, treatment history, toxicity, response to therapy, subsequent therapy, and survival data. Disease was characterized according to the International Staging System [24] and chromosomal abnormalities determined by standard metaphase karyotype and/or fluorescence in situ hybridization (FISH). Treatment-induced adverse events were graded according to the National Cancer Institute common terminology criteria for adverse events (CTCAE) version 4.0. For response assessment we utilized the International Uniform Response Criteria for Mutiple Myeloma [25]. The main endpoint of the study was to determine the overall response rate for high-dose cyclophosphamide in bortezomib-refractory MM patients. Secondary endpoints were to determine median overall survival, frequency and severity of adverse events. Progression free survival and duration of response was not estimated since this endpoint was distorted by the high proportion of patients undergoing transplantation immediately after a response was obtained. We reported proportions with their respective 95% confidence intervals. Continuous numerical variables were described using their median and range. Overall survival was described utilizing the method of Kaplan-Meier. Statistical analysis was performed the software SPSS (version 16). Guillermo L. Rivell*, Chris Y. Brunson , Laura Milligan*, Robert K. Stuart*, Luciano J. Costa costalj@musc.edu*, * Division of Hematology and Oncology, Medical University of South Carolina, Charleston, South Carolina, Mabry Cancer Center, Orangeburg, South Carolina.